Tamper Resistant Co-Extruded Dosage Form Containing an Active Agent and an Adverse Agent and Process of Making Same

ABSTRACT

The present invention relates to co-extruded pharmaceutical compositions and dosage forms including an active agent, such as an opioid agonist, and an adverse agent, such as an opioid antagonist. Such compositions and dosage forms arc useful for preventing or discouraging tampering, abuse, misuse or diversion of a dosage form containing an active pharmaceutical agent, such as an opioid. The present invention also relates to methods of treating a patient with such a dosage form, as well as kits containing such a dosage form with instructions for using the dosage form to treat a patient.

1. FIELD OF THE INVENTION

The present invention relates to co-extruded pharmaceutical compositionsand dosage forms including an active agent, such as an opioid agonist,and an adverse agent, such as an opioid antagonist, which are useful forpreventing or discouraging tampering, abuse, misuse or diversion of thedosage form. The present invention also relates to methods of treating apatient with such a dosage form, as well as kits containing such adosage form with instructions for using the dosage form to treat apatient. The present invention further relates to a co-extrusion processfor the preparation of such pharmaceutical compositions and dosageforms.

2. BACKGROUND OF THE INVENTION

There have been previous attempts in the art to increase the tamperresistance of dosage forms, such as opioid analgesic dosage forms. Priorapproaches to developing tamper resistant opioid dosage forms haveincluded combining an opioid agonist with an opioid antagonist.Particular examples of such combinations include compositions includingnaloxone and morphine or oxymorphone (U.S. Pat. No. 3,493,657 toLewenstein et al.); methadone and naloxone (U.S. Pat. No. 3,773,955 toPachter et al.); methadol or acetyl methadol and naloxone (U.S. Pat. No.3,966,940 to Pachter et al.); oxycodone and naloxone (U.S. Pat. No.4,457,933 to Gordon et al.); and buprenorphine and naloxone (U.S. Pat.No. 4,582,835 to Lewis et al.).

U.S. Pat. No. 6,228,863 to Palermo et al. discloses an oral dosage formwhich combines an opioid agonist and an opioid antagonist such that atleast two separation steps are required to isolate the agonist.

U.S. Pat. No. 5,935,975 to Rose et al. discloses methods for treatingdrug dependency by the combined administration of the drug, i.e. theagonist, and an antagonist of the drug.

U.S. Patent Application Publication No. 2003/0143269 A1 to Oshlack etal. discloses a dosage form comprising an opioid against in releasableform and a sequestered opioid antagonist which is not substantiallyreleased following administration of the intact dosage form.

In addition, it is known in the pharmaceutical art to prepare oraldosage forms which provide for controlled release of therapeuticallyactive agents. Such controlled release compositions are used to delayabsorption of at least a portion of the dose of the agent until it hasreached certain portions of the gastrointestinal tract. Such controlledrelease of the agent serves to maintain a desired concentration of theagent in the blood stream for a longer duration than would occur ifconventional immediate or rapid release dosage forms were to beadministered.

Over the years, several different methods of preparing controlledrelease pharmaceutical dosage forms have been suggested, including, forexample, extrusion, granulation, coating beads and the like.

There remains a need in the art for improved tamper resistant dosageforms and improved techniques for their preparation.

3. SUMMARY OF THE INVENTION

The present invention relates to co-extruded pharmaceutical compositionsand dosage forms including an active agent and an adverse agent, and toco-extrusion methods of making such compositions and dosage forms. Thepresent invention also relates to methods of treating a patient withsuch pharmaceutical compositions or dosage forms, as well as kitsincluding such pharmaceutical compositions or dosage forms andinstructions directing the usage of the composition or dosage form totreat a patient. The dosage forms in accordance with the presentinvention include oral dosage forms, including but not limited to,capsules or tablets, rectal suppositories and vaginal suppositories. Thedosage forms comprise co-extruded compositions, including but notlimited to one or more particles such as melt-extruded multiparticulates(“MEMs”) made by a process comprising co-extrusion.

In one embodiment, the present invention relates to a co-extruded dosageform including a core comprising an adverse agent, and one or more shelllayers or components comprising an active agent. In this embodiment, theshell layers or components at least partially surround the core, andpreferably, surround a majority of the core. The dosage form is made bya process which comprises co-extrusion of the core and the shell.

In another embodiment, the invention relates to a co-extruded dosageform including a core, a sheath comprising one or more sheath layers orcomponents, and a shell comprising or more shell layers or components.The dosage form is made by a process which comprises co-extrusion of thecore, the sheath and the shell. In this embodiment, the core comprisesan adverse agent, the sheath comprises a hydrophobic material and atleast partially surrounds the core, and the shell comprises an activeagent at least partially surrounds the sheath.

Advantageously, in one embodiment, the shell can provide a controlledrelease of the active agent upon administration to a patient. Also, inone embodiment, the sheath component can contribute to delaying and/orreducing the in vivo release of adverse agent contained in the core.

In one embodiment, the invention is directed to a method of making atamper-resistant dosage form comprising a) forming a multilayerextrudate by co-extruding a core comprising an adverse agent and a shellcomprising an active agent which at least partially surrounds thesheath; and b) rendering the mutlilayer extrudate to form at least oneparticle. In one embodiment, a rolling punch is used to render themultilayer extrudate into one or more particles.

In one embodiment, the present invention includes a method of making atamper-resistant dosage form comprising a) forming a multilayerextrudate by co-extruding a core comprising an adverse agent and ahydrophobic material; a sheath comprising a hydrophobic material whichat least partially surrounds the core; and a shell comprising an activeagent and a hydrophobic material which at least partially surrounds thesheath; b) using a rolling punch to form one more particles from themultilayer extrudate; and c) incorporating one or more particles into adosage form.

The compositions and dosage forms of the present invention can provideimmediate release or controlled release of the active agent.

In certain embodiments, the adverse agent can be sequestered. Thesequestered adverse agent can be present in the core, and in oneembodiment, the adverse agent can be present only in the core of thedosage form.

The present invention further relates to methods of treating a patientincluding administering a dosage form of the invention to the patient.In one embodiment of the invention, the patient is treated for pain.

The present invention also includes a method of reducing abuse, misuseor diversion of a dosage form for treating pain, which method includesadministering to a patent in need thereof a dosage form of theinvention.

In still another embodiment, the invention relates to a kit for treatinga patient, including at least one dosage form of the invention and a setof instructions describing the use of the dosage form to treat thepatient. In one embodiment of the invention, the kit is for treating apatient's pain.

The present invention can be understood more fully by reference to thefollowing detailed description and examples, which are intended toexemplify non-limiting embodiments of the invention.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 a, 1 b and 1 c shows perspective views of embodiments of adosage form of the present invention.

FIG. 2 illustrates one embodiment of the invention in which particulatesof the invention are prepared from a multi-layer sheet using a rollingpunch.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Definitions

Any reference herein to any pharmaceutical agent, such as an activeagent, an adverse agent, an opioid agonist or an opioid antagonist,shall, unless otherwise stated, include any pharmaceutically acceptableform of such pharmaceutical agent, such as the free form, anypharmaceutically acceptable salt form, any pharmaceutically acceptablebase form, any pharmaceutically acceptable hydrate, any pharmaceuticallyacceptable solvate, any stereoisomer, any optical isomer, as well as anyprodrug of such pharmaceutical agent and any pharmaceutically activeanalog of such pharmaceutical agent, and mixtures of any two or more ofthe foregoing.

The phrase “pharmaceutically acceptable salt,” as used herein, can be asalt formed from an acid and the basic group, such as a nitrogen group,of an active agent or an adverse agent. Generally, examples of suchsalts include, but are not limited, to sulfate, citrate, acetate,oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidphosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate,oleate, tannate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, glubionate and palmoate(i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” can alternatively be a salt preparedfrom an active agent or an adverse agent having an acidic functionalgroup, such as a carboxylic acid or sulfonic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Generally,examples of such bases include, but are not limited to, hydroxides ofalkali metals such as sodium, potassium, and lithium; hydroxides ofalkaline earth metal such as calcium and magnesium; hydroxides of othermetals, such as aluminum and zinc; ammonia, and organic amines, such asunsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;dicyclohexylamine; tributyl amine; pyridine; N-methylamine,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N,-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

A “patient” or an “animal” is preferably a mammal, and includes, but isnot limited to, a cow, monkey, horse, sheep, pig, chicken, turkey,quail, cat, dog, mouse, rat, rabbit, and guinea pig, and most preferablya human.

As used herein, the phrase “active agent” refers to a pharmaceuticalagent that causes a biological effect when absorbed in sufficient amountinto the blood stream of a patient.

As used herein, the phrase “adverse agent” refers to a pharmaceuticalagent that partially or completely negates or reverses at least onebiological effect of an active agent present in the dosage form, e.g.euphoric effect, or produces one or more unpleasant physiologicalreactions, e.g., vomiting, nausea, diarrhea, bad taste, when absorbed insufficient amount into the blood stream of a patient or animal.

As used herein, the term “controlled release” refers to the in vivorelease of an active agent from a dosage form following administrationat a rate which will provide a longer duration of action than a singledose of the immediate release dosage form. For example, a typicalimmediate release oral dosage form can release the drug, e.g., over a 1hour interval, as compared to a controlled release oral dosage formwhich can release the drug, e.g., over a 5 to 24 hour interval.

As used herein, the term “layer” refers to a coating or stratumincluding, but not limited to, a coating of stratum having a singlethickness; a coating or stratum having multiple thicknesses; a coatingor stratum having opposing surfaces which are parallel; a coating orstratum having opposing surfaces which are not parallel; a coating orstratum having one or more surfaces which are planar; and a coating orstratum having one or more surfaces which are non-planar.

As used herein, the term “laminate” refers to a structure comprisingmore than one layer, i.e., a multilayer structure.

As used herein, the phrase “opioid agonist” refers to an active agentwhich binds, optionally stereospecifically, to any one or more ofseveral subspecies of opioid receptors and produces agonist activity.

As used herein, the phrase “opioid antagonist” refers to an adverseagent that either reduces, delays or reverses at least one biologicaleffect of an opioid agonist, e.g., euphoric effect, when absorbed insufficient amount into the blood stream of a patient or animal.

5.2 Co-Extruded Dosage Forms Including an Active Agent and an AdverseAgent

As stated above, the present invention is directed to co-extrudedpharmaceutical compositions and dosage forms including an active agentand an adverse agent, and to co-extrusion methods of making suchcompositions and dosage forms. In one embodiment, the invention relatesto dosage forms including one or more co-extruded particles comprisingan active agent and an adverse agent.

The compositions and dosage forms of the invention can provide immediaterelease or controlled release of the active agent.

In certain embodiments, the adverse agent is not sequestered. In thoseembodiments, the adverse agent can be released in vivo at any rate,including immediate release and controlled release.

In certain embodiments, the adverse agent is sequestered. In thoseembodiments, the compositions and dosage forms of the invention areformulated or made in a manner which greatly reduces or prevents the invivo release or absorption of the sequestered adverse agent into theblood stream following administration as intended of the intact dosageform to a patient. Thus, only a small amount, preferably less than about10% by weight and more preferably less than about 1% by weight or none,of the sequestered adverse agent present in the dosage form is releasedin vivo or absorbed into the blood stream following the administrationas intended of an intact dosage from to a patient. When the sequesteredadverse agent is an opioid antagonist, in certain embodiments,preferably less than about 0.5 mg, and more preferably less than about0.05 mg, of the opioid antagonist is released in vivo followingadministration as intended of the intact dosage form to a patient. Forexample, in one embodiment, when the sequestered adverse agent isnaltrexone, preferably less than 0.0625 mg of naltrexone is released invivo following administration as intended of the intact dosage form to apatient.

In one embodiment, the adverse agent can be sequestered by extruding theadverse agent with at least one hydrophobic material and, optionally,binders, plasticizers, processing aids, excipients, or the like, orcombinations of two or more of the foregoing. U.S. Patent ApplicationPublication No. 2003/0143269 A1, which is expressly incorporated hereinin its entirety for all purposes, discloses compositions and methods forformulating a dosage form comprising a sequestered adverse agent and anactive agent. In one embodiment, the dosage form comprises a sequesteredadverse agent present within a core which is at least partially coveredor surrounded by one or more sheath layers or components, and the sheathcomponents are at least partially surrounded by one or more shell layersor components comprising an active agent. The dosage form is produced bya process which comprises a co-extrusion of the core, the sheathcomponent(s) and the shell component(s). In one embodiment, the core isat least partially surrounded or covered by the sheath, and a portion ofthe adverse agent-containing core can be exposed. The sheath cancomprise two sheath layers or components that cover or surround at leasta portion of, preferably a majority, of the core. In one embodiment, thesheath covers or surrounds a majority of the top and bottom of the core,while leaving some or all of the sides of the core uncovered. In oneembodiment, the sheath covers or surrounds substantially all of the top,the bottom and the sides of the core.

In one embodiment, the sheath is at least partially surrounded orcovered by the shell, and preferably a majority of the sheath issurrounded or covered by the shell. The shell can comprise two shelllayers or components. In one embodiment, the shell covers or surrounds amajority of the top and bottom of the sheath, while leaving some or allof the peripheral surface or sides of the sheath uncovered. In oneembodiment, the shell covers or surrounds substantially all of the top,the bottom and the sides of the sheath.

In certain embodiments, the sheath does not cover or surround all of thecore. In those embodiments, a portion of the shell can be adjacent toand cover or surround some or all of the portion of the core which isnot covered or surrounded by the sheath.

In one embodiment, the present invention relates to solid dosage formsincluding a plurality of co-extruded particles including an active agentand an adverse agent, wherein the particles comprise a core containingthe adverse agent and the core is at least partially surrounded by ashell comprising the active agent. The particles are made by a processcomprising co-extrusion of the core and the shell. Preferably, the shellsurrounds a majority of the core component. The core can include anadverse agent and a hydrophobic material, and the shell can include anactive agent and a hydrophobic material. In one embodiment, the adverseagent is sequestered.

In certain embodiments, the adverse agent can be present throughout thecore. In one embodiment, the adverse agent can be present in both thecore and the sheath. In another embodiment, the adverse agent can bepresent in one or more inner layers of a multilayer particle.

In certain embodiments, the sheath does not include any adverse agent oractive agent. In other embodiments, the sheath can include an adverseagent and/or an active agent. In one embodiment, the amount of adverseagent present in the sheath is less than the amount present in the core.Similarly, in one embodiment, the amount of active agent present in thesheath is less than the amount present in the shell.

In certain embodiments, the shell does not include any adverse agent. Inother embodiments, the shell can include an adverse agent. In oneembodiment, the amount of adverse agent present in the shell is lessthan the amount of adverse agent present in the core. If present, theadverse agent included in the shell can be immediate release orcontrolled release, or can be sequestered.

In one embodiment, the adverse agent is present only in the core, theactive agent is present only in the shell, and there is no adverse agentor active agent present in the sheath of the dosage form as co-extruded.In this embodiment, it is acceptable for small amounts of active agentand/or adverse agent to migrate to other components or layers followingco-extrusion.

The dosage forms of the invention can be administered orally, such as inthe form of a tablet or capsule; or rectally or vaginally, such as inthe form of a suppository. In a preferred embodiment, the invention isdirected to oral dosage forms.

The dosage forms of the invention can comprise one or more co-extrudedparticles of any appropriate size. In one embodiment, the dosage formcan comprise a plurality of small particles, such as, for example,particles having a size of from about 0.1 mm to about 5.0 mm in alldimensions. In another embodiment, the particles have a dimension offrom about 0.1 mm to about 3.0 mm in all dimensions. The particles canhave any shape, such as cylindrical, spherical, square, ellipsoid, orany regular or irregular form, as desired.

In one embodiment, an oral dosage form is prepared to include aneffective amount of melt-extruded multiparticulates (“MEMs”) within ahard or soft gelatin capsule. For example, a plurality of MEMscontaining a core, a sheath and a shell can be placed in a gelatincapsule in an amount sufficient to provide an effectivesustained-release dose of the active agent when ingested and contactedby body fluid, without significant release of the sequestered adverseagent. The particle size of the multiparticulates of the dosage form ofthe invention is from about 0.1 mm to about 5.0 mm in all dimensions; inanother embodiment, from about 0.1 mm to about 3.0 mm in all dimensions.

In another embodiment, a plurality of particles or MEMs can becompressed into tablets, for example, by the procedures set forth inU.S. Pat. No. 4,957,681 (Klimesch, et al.), which is expresslyincorporated herein by reference in its entirety for all purposes.Techniques and compositions for making tablets (compressed and molded),capsules (hard and soft gelatin) and other forms of pills are alsodescribed in Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (1980), incorporated by reference herein in its entirety forall purposes.

In another embodiment, a tablet can be prepared by forming a co-extrudedextrudate into tablets using devices such as a molding roll, a pinchdevice, a belt and a roller or tow rollers. In another embodiment, atablet can be prepared from an extrudate sheet using a rolling punch, asshown in FIG. 2.

It is to be understood that the tablets can be any geometrical shapesuch as, for example, spherical, oval, pellet, etc., and can vary insize in any dimension depending on the method of manufacture and thepatient. The tablet can have a dimension in any direction from about 5mm to about 75 mm. In one embodiment, the tablet has a dimension in anydirection from about 5 mm to about 30 mm. In another embodiment, thetablet has a dimension in any direction from about 5 mm to about 15 mm.

The particles or tablets of the invention can further comprisepharmaceutically acceptable hydrophobic coating materials as definedabove in Section 5.5; excipients such as binding agents (e.g.,pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talcor silica); disintegrants (e.g., potato starch or sodium starchglycolate); wetting agents (e.g., sodium lauryl sulphate); and otheradditives or excipients or as is well-known in the art. The particles ortablets can be coated by methods well-known in the art provided suchcoating does not interfere with the intended use. Non-limiting examplesof coating processes are spray coating and dip coating.

In certain embodiments, the dosage forms are formulated to providecontrolled release of the active agent in vivo, e.g., over about 5 to 8hours or longer, preferably over at least 12 hours, more preferably overat least 24 hours, or longer.

While it is contemplated by the inventors that, for certain purposes,the release rate of the active agent and the adverse agent can bemeasured by in vivo methods or in vitro methods, the inventors do notrepresent that there is a direct correlation between the resultsobtained via the two different methods.

When administered as intended to a patient, the in vivo release of anyadverse agent from the intact dosage form will preferably besufficiently low so that it will not substantially reduce the benefitsof the active agent or produce any unpleasant physiological reaction.The release rate of the adverse agent will be determined in large partby the composition of the core, the sheath and the shell. The dosageform of the invention will typically release less than about 10% byweight of, preferably less than about 1% by weight of, more preferablysubstantially no sequestered adverse agent in vivo followingadministration as intended of the intact dosage form. When thesequestered adverse agent is an opioid antagonist, the dosage form willpreferably release less than about 0.5 mg, more preferably less thanabout 0.05 mg, of the opioid antagonist in vivo following administrationas intended of the intact dosage form. For example, in one embodiment,when the adverse agent is naltrexone opioid antagonist, preferably lessthan 0.0625 mg of naltrexone is released in vivo followingadministration of the intact dosage form as intended.

In certain embodiments, the dosage form preferably releases less thanabout 10% by weight, more preferably less than about 1% by weight, morepreferably substantially no adverse agent over a 36 hour period during astandard in vitro dissolution test. For example, when the oral dosageform contains 5.0 mg of sequestered opioid antagonist and a dissolutiontest is conducted using the USP Basket Method (USP Type I basket, 100rpm; 700 ml simulated gastric filled, pH 1.2 without enzyme; 37° C. for1 hour followed by 900 ml simulated intestinal fluid; pH 7.5 withoutenzyme for the duration of the test), the quantity of opioid antagonistreleased in simulated gastrointestinal fluid over 36 hours can be lessthan 0.5 mg, and more preferably less than 0.05 mg.

When an intact dosage form including an active agent and a sequesteredadverse agent is administered to a patient, only a small amount, andpreferably almost none, of the sequestered adverse agent is released invivo, whereas the active agent is released at the intended rate, whichcan vary from immediate release to controlled release. However, when adosage form including an active agent and a sequestered adverse agentparticles is tampered with, e.g., chewed, crushed, ground or dissolved,particularly in a solvent with heat (e.g., greater than from about 45°C. to about 50° C., up to about 100° C. or above), then the amount ofadverse agent available for absorption into the body is substantiallyincreased. The adverse agent is then available to exert its effect byeither reducing at least one effect of the active agent, e.g., euphoriceffect, or eliciting one or more unpleasant effects in the patient.Thus, where the adverse agent is an antagonist of the active agent, atleast one effect of the active agent is preferably substantiallydiminished, or even eliminated, by the effect of the adverse agent. Forexample, where the active agent is an opioid agonist and the adverseagent is an opioid antagonist, an increased amount of opioid antagonistwill become bioavailable when the dosage form is tampered with,interfering with opioid-receptor binding and reducing the opioidagonist's euphoric effect. Accordingly, only patients who take thedosage form of the present invention as intended as an intact dosageform will experience substantially the full pharmacological effect ofthe active agent. Where the adverse agent is an emetic agent and thedosage form is tampered with, the release and absorption of the emeticagent will induce nausea and/or vomiting to discourage the user fromtampering with the dosage form and also, in certain instances, to removethe active agent from the subject's body. Abuse of the active agent inthe dosage form will thus become less desirable because of theundesirable effects caused by the adverse agent.

In one embodiment of the invention, the solid dosage form can optionallybe covered by a cosmetic coating. Any known type of cosmetic coatingused for pharmaceutical dosage forms can be used so long as the releaseof the coated dosage form achieves the intended purpose of theinvention.

In certain embodiments, the dosage form can be cured by exposure toprolonged elevated temperatures in order to achieve increased stability.As used herein, the term “curing” means the heat treatment of the dosageform (or intermediate product) for purposes of obtaining a stabilizedfinal dosage form. As understood by those skilled in the art, when theformulations of the invention incorporate a polymer as part or all ofthe hydrophobic retarding agent, a heat treatment causes a curing effectand the polymer possibly cross-links with itself into a more stablestate. When the formulations of the invention include a hydrophobicmaterial such as, e.g., hydrogenated vegetable oil or stearyl alcohol,the heat treatment can be more akin to an annealing of the formulationrather than a curing of the polymer. However, for purposes of thepresent invention, the use of the term “curing” is deemed to encompassboth curing and annealing. In situations where the hydrophobic materialincludes only a wax-like substance, curing can be accomplished at atemperature from about 35° C. to about 65° C., for a time periodsufficient to achieve maximum stability, such as for a time period fromabout 4 to about 72 hours. In other embodiments, curing is conducted ata temperature of from about 40° C. to about 60° C., for a time periodfrom about 5 to about 48 hours or more, and preferably at least about 24hours. Suitable curing times that achieve the intended result of astabilized dosage form can be determined by those of skill in the art.

5.3 Active Agent

Any kind of active agent can be used in the co-extruded dosage forms ofthe present invention. Examples of useful active agents include, but arenot limited to, analgesics, anti-inflammatory agents, anthelmintics,anti-arrhythmic agents, anti-bacterial agents, anti-viral agents,anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics,anti-fungal agents, anti-gout agents, anti-hypertensive agents,anti-malarials, anti-migraine agents, anti-muscarinic agents,anti-neoplastic agents, erectile-dysfunction-improvement agents,immunosuppressants, anti-protozoal agents, anti-thyroid agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, β-blockers,cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonianagents, gastrointestinal agents, histamine receptor antagonists,keratolytics, lipid regulating agents, anti-anginal agents,cox-2-inhibitors, leukotriene inhibitors, macrolides, muscle relaxants,nutritional agents, opioid analgesics, protease inhibitors, sexhormones, stimulants, muscle relaxants, anti-osteoporosis agents,anti-obesity agents, cognition enhancers, anti-urinary incontinenceagents, nutritional oils, anti-benign prostate hypertrophy agents,essential fatty acids, and non-essential fatty acids. The dosage formscan comprise more than one active agent.

More specific examples of active agents include, but are not limited to,opioids, benzodiazepines, barbiturates, and stimulants, such asmethylphenidate and amphetamines, dronabinol, glutethimide,methylphenidate, nabilone, anabolic steroids, methylprylon,ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline,levomethadyl, benzphetamine, chlorphentermine, diethylpropion,phentermine, mebutamate, chlortermine, phenylacetone, dronabinol,nabilone, benphetamine, chloral hydrate, ethclorovynol, paraldehyde,midazolam, and detropropoxyphene.

In certain embodiments, the active agent is an opioid agonist. Usefulopioid agonists include, but are not limited to, alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydromorphodone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine,norpipanone, opium, oxycodone, oxymorphone, pantopon, papaveretum,paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propoxyphene, propylhexedrine,sufentanil, tilidine, tramadol, pharmaceutically acceptable saltsthereof, and mixtures of any two or more of the foregoing.

In certain embodiments, the opioid agonist is selected from the groupconsisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine,levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyland derivatives thereof, dipipanone, heroin, tramadol, etorphine,dihydroetorphine, butorphanol, levorphanol and mixtures thereof. In oneembodiment, the opioid agonist is oxycodone, hydromorphone orhydrocodonc.

The term “benzodiazepines” refers to benzodiazepine and drugs that arederivatives of benzodiazepine and are able to depress the centralnervous system. Benzodiazepines include, but are not limited to,alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam,estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam,oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate andmixtures of any two or more of the foregoing.

Barbiturates refer to sedative-hypnotic drugs derived from barbituricacid (2,4,6,-trioxohexahydropyrimidine). Barbiturates include, but arenot limited to, amobarbital, aprobarbotal, butabarbital, butalbital,methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital,secobarbital and mixtures of any two or more of the foregoing.

Stimulants refer to drugs that stimulate the central nervous system.Stimulants include, but are not limited to, amphetamines, such asamphetamine, dextroamphetaminc resin complex, dextroamphetaminc,methamphetamine, methylphenidate and mixtures of any two or more of theforegoing.

The active agent can be an agent intended for delivery to the colon,including, but not limited to, agents that act locally in the colonicregion to treat a colon diseases such as irritable bowel syndrome,irritable bowel disease, Crohns disease, constipation, post operativeatony, gastrointestinal infections, and therapeutic agents that deliverantigenic material to the lymphoid tissue. Active agents for thetreatment of colon disease include, but are not limited to 5-ASA;steroids, such as hydrocortisone and budesonide; laxatives; stoolsofteners; octreotide; cisapride; anticholinergics; opioids; calciumchannel blockers; DNA for delivery to the cells of the colon;glucosaminc; thromboxane A₂ synthetase inhibitors, such as Ridogrel;5HT3-antagonists, such as ondansetron; antibodies against infectiousbacteria, such as Clostridium difficile; and antiviral agents, forexample, for the prophylaxis of HIV.

Alternatively, the active agent can be an agent that is systemicallyactive and for which absorption is improved in the colon region. Suchdrugs include polar compounds such as: heparins; insulin; calcitonins;human growth hormone (HGH); growth hormone releasing hormone (GHRH);interferons; somatostatin and analogues such as octreotide andvapreotide; erythropoietin (EPO); granulocyte colony stimulating factor(GCSF); parathyroid hormone (PTH); luteinising hormone releasing hormone(LHRH) and analogues thereof; atrial natriuretic factor (ANF);vasopressin; desmopressin; calcitonin gene related peptide (CGRP); andanalgesics.

The active agent particles can further comprise hydrophobic materials,binders, plasticizers, excipients, and combinations of any two or moreof the foregoing. Suitable matrix materials include those which allowrelease of the active agent at a rate sufficient to achieve the desiredresult, e.g., immediate release or sustained release. In one embodiment,permeable matrix material is used, allowing for diffusive release of theactive agent into the gastrointestinal fluid.

5.4 Adverse Agent

As noted above, the present invention is directed to co-extruded dosageforms and pharmaceutical compositions including an active agent and anadverse agent, which can be sequestered, as well as co-extrusion methodsfor making and administering such dosage forms and compositions. In oneembodiment, the invention relates to dosage forms including a pluralityof particles including a an active agent and an adverse agent, which canbe sequestered.

The adverse agent can be any pharmaceutical active agent which at leastpartially reduces or blocks the biological effect of an active agent orwhich creates an unpleasant effect when absorbed into an animal's orpatient's blood stream. Examples of adverse agents include, but are notlimited to, antagonists of any therapeutically active agonist. When anopioid agonist is used as the active agent in the dosage form of thepresent invention, an opioid antagonist can be used as the adverseagent. Likewise, when a benzodiazepine is used as the active agent inthe dosage form of the present invention, a benzodiazepine antagonistcan be used as the adverse agent. When a barbiturate is used as anactive agent in the dosage form of the present invention, a barbiturateantagonist can be used as the adverse agent. When an amphetamine is usedas an active agent in the dosage form of the present invention, anamphetamine antagonist can be used as the adverse agent. When the activeagent is toxic when dosed above its normal therapeutic range, i.e., whenthere is a significant potential for an overdose, then an antidote ofthe toxic active agent can be used as the adverse agent.

In one embodiment, the adverse agent is an opioid antagonist. Opioidantagonists useful in the present invention include, but are not limitedto, naloxone, naltrexone, nalmefene, nalbuphine, nalorphine,cyclazacine, cyclazocine, levallorphan, pharmaceutically acceptablesalts thereof, and mixtures of any two or more of the foregoing.

Useful opioid antagonist salts include salts formed from an acid and thebasic nitrogen group of an opioid antagonist. Examples of opioidantagonist salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and palmoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

Other opioid antagonist salts include salts prepared from an antagonisthaving an acidic functional group, such as a carboxylic acid or sulfonicacid functional group, and a pharmaceutically acceptable inorganic ororganic base. Suitable bases include, but are not limited to thoseidentified above in Section 5.1 in the paragraph which references theterm “pharmaceutically acceptable salt”.

In certain embodiments, the opioid antagonist is nalmefene, naloxone,naltrexone, or a pharmaceutically acceptable salt thereof. In anotherembodiment, the opioid antagonist is a naltrexone salt, such asnaltrexone hydrochloride.

Benzodiazepine antagonists that can be used as the adverse agent of thepresent invention include, but arc not limited to, flumazcnil.

Barbiturate antagonists which can be used as the adverse agent of thepresent invention include, but are not limited to, amphetamines, asdescribed herein.

Stimulant antagonists that can be used as the adverse agent of thepresent invention include, but are not limited to, benzodiazepines,described herein.

In another embodiment of the present invention, the adverse agent is anagent that causes an undesired physiological reaction, such as emesis.This type of adverse agent can be used with any kind of therapeuticagent including an opioid, a benzodiazepine, a barbiturate, or astimulant. Examples of emetic agents suitable for use as the adverseagent in the present invention includes any drug that safely andeffectively induces vomiting after administration including, but notlimited to, ipecac and apomorphinc

5.5 Core

In certain embodiments the present invention, the adverse agent, whichcan be sequestered, can be present in the core or in an inner layer of aco-extruded, multi-layer particle. In one embodiment, the adverseagent-containing core of the present invention preferably includes ahydrophobic matrix material. Hydrophobic matrix materials useful in thepresent invention include those that are known in the art to beinsoluble or to have a low solubility in the gastrointestinal tract.Such materials include, but are not limited to, a hydrophobic materialselected from the group consisting of acrylic and methacrylic acidpolymers and copolymers, and alkylcelluloses. The matrix can alsoinclude additional hydrophobic materials such as zein, shellac,hydrogenated castor oil, hydrogenated vegetable oil or mixtures thereof.Although insoluble, such hydrophobic materials can degrade over time,thereby eventually releasing some portion of the adverse agent. One ofordinary skill in the pharmaceutical arts can control the rate of suchrelease by, for example, altering the content of the hydrophobic matrixmaterial in the adverse agent core in order to alter the in vivo releaseof the adverse agent.

In one embodiment, the hydrophobic matrix material includes acrylicpolymers. Examples of suitable acrylic polymers include, but are notlimited to acrylic acid and methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylates, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymers,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, poly(methacrylic acid) (anhydride), methyl methacrylate,polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acidanhydride), and glycidyl methacrylate copolymers. Additional examples ofsuitable acrylic polymers include, but are not limited to, acrylicresins including copolymers synthesized from acrylic and methacrylicacid esters (e.g., the copolymer of acrylic acid lower alkyl ester andmethacrylic acid lower alkyl ester) containing about 0.02 to 0.03 molesof a tri (lower alkyl) ammonium group per mole of acrylic andmethacrylic monomer.

The acrylic polymer can comprise one or more ammonio methacrylatecopolymers. Ammonio methacrylate copolymers are well known in the art,and are fully polymerized copolymers of acrylic and methacrylic acidesters with a low content of quaternary ammonium groups. In order toobtain a desirable dissolution profile for a given therapeutic agent, itmight be necessary to incorporate two or more ammonio methacrylatecopolymers having differing physical properties. For example, it isknown that by changing the molar ratio of the quaternary ammonium groupsto neutral (meth)acrylic esters, the permeability properties of theresultant coating can be modified. One of ordinary skill in the art willreadily be able to combine monomers to provide a copolymer that releasesthe therapeutic agent at the desired release rate. Copolymers ofacrylate and methacrylate having a quaternary ammonium groupfunctionality are commercially available as EUDRAGIT RS™ and EUDRAGITRL™ (Röhm Pharma, GmbH, Weiterstat, Germany). Preferred ammoniomethacrylate resins include EUDRAGIT RS™ in all forms, such as EUDRAGITRS PO™. EUDRAGIT RS™ is known to be a water-insoluble copolymer of ethylacrylate (EA), methyl methacrylate (MM) and trimethylammonium ethylmethacrylate chloride (TAM) in which the molar ratio of EA:MM:TAM is1:2:0.01; see, e.g., U.S. Pat. No. 6,306,391. EUDRAGIT RS PO™ is knownto be a powdered form of EUDRAGIT RS™; see, e.g., U.S. Pat. No.5,492,692.

In one embodiment the hydrophobic matrix material includes a waterinsoluble cellulose polymer. In certain embodiments, the cellulosepolymer is a cellulose ether, a cellulose ester, or a cellulose esterether. Preferably, the cellulose polymers have a degree of substitution(“D.S.”) on the anhydroglucose unit of from about zero up to andincluding about 3. As used herein the term D.S. means the average numberof hydroxyl groups present on the anhydroglucose unit of the cellulosepolymer that are replaced by a substituent group. Representativecellulose polymers include, but are not limited to, polymers selectedfrom cellulose acylate, cellulose diacylate, cellulose triacylate,cellulose acetate, cellulose diacetate, cellulose triacetate, mono-,di-, and tricellulose alkanylates, mono-, di-, and tricellulosearoylates, and mono-, di-, and tricellulose alkenylates. Exemplarycellulose polymers include cellulose acetate having a D.S. of from about1 to about 2 and cellulose acetate having a D.S. of from about 2 toabout 3. Preferably, the cellulose polymer is ethylcellulose, celluloseacetate, cellulose propionate (low, medium, or high molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, or cellulose triacetate. A more preferred celluloseis ethylcellulose.

More specific cellulose polymers include cellulose propionate having aD.S. of about 1.8; cellulose acetate butyrate having a D.S. of about1.8; cellulose triacylate having a D.S. of about 2.9 to 3, such ascellulose triacetate, cellulose trivalerate, cellulose trilaurate,cellulose tripalmitate, cellulose trisuccinate, and cellulosetrioctanoate; cellulose diacylates having a D.S. of about 2.2 to 2.6such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentanoate; and coesters of cellulose such ascellulose acetate butyrate, cellulose acetate octanoate butyrate, andcellulose acetate propionate.

In certain embodiments, the core can generally comprise from about 30%to about 99% by weight of one or more hydrophobic matrix materials,preferably from about 50% to about 95% by weight of the one or morehydrophobic matrix materials, more preferably from about 60% to about95% by weight of the one or more hydrophobic matrix materials.

The adverse agent-containing core can optionally comprise one or morebinders, additional retardants, plasticizers, and/or excipients. Bindersare useful for maintaining the integrity of the matrix and can also helpto delay the release of an agent into the bodily fluid. Examples ofbinders include natural and synthetic waxes, water insoluble waxes,fatty alcohols, fatty acids, hydrogenated fats, fatty acid esters, fattyacid glyercides, hydrocarbons, and hydrophobic and hydrophilic polymershaving hydrocarbon backbones, and mixtures such as, stearyl alcohol,stearic acid, and water soluble polymers such as hydroxycclluloses.

Plasticizers are useful when the hydrophobic matrix material containscellulose polymer or an acrylic polymer. Non-limiting examples ofsuitable plasticizers include, e.g., acetyl triethyl citrate and/oracetyl tributyl citrate.

The adverse agent core can also include other excipients, which can beadded to improve the processability of the formulation during extrusionand/or to improve the properties of the final product. Non-limitingexamples of liquid excipients include water and oils, including those ofpetroleum, animal, vegetable, or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil, castor oil, triglycerides and thelike. Examples of solid excipients include magnesium stearate, saline,gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, ureaand the like. Coloring agents can also be added to the core.

In certain embodiments, the core can comprise one or more of thematerials disclosed in Section 5.7 with respect to the shell of thedosage form of the present invention.

5.6 Sheath

In certain embodiments, the dosage form of the present invention caninclude a sheath which at least partially surrounds the adverseagent-containing core, and preferably surrounds a majority of theadverse agent-containing core. In certain embodiments, the sheathpreferably includes a hydrophobic matrix material and, optionally,binders, additional retardants, plasticizers and excipients. While, incertain embodiments, the sheath can contain adverse agent and/or activeagent, it is preferred that the sheath does not contain any adverseagent or active agent.

In one embodiment, the hydrophobic material of the sheath includes oneor more materials selected from the group consisting of acrylic andmethacrylic acid polymers and copolymers, and water insolublealkylcelluloses as described above for the core. The sheath canoptionally comprise one or more additional hydrophobic materials, suchas shellac, zein, hydrogenated castor oil, hydrogenated vegetable oiland mixtures thereof, as described above for the core.

The hydrophobic matrix material used in the sheath can be the same as ordifferent from that used in the adverse agent core. Although thehydrophobic material used in the sheath will preferably be substantiallyinsoluble in the gastrointestinal tract, this material could dissolve orbiodegrade in vivo to some limited extent over time, thereby permittingthe in vivo release from the core of a small amount of sequesteredadverse agent. One of ordinary skill in the pharmaceutical arts canalter the rate of such release, for example, by altering the compositionof the sheath, increasing the thickness of the sheath, surrounding alarger portion of the core with the sheath, varying the size and/ordimensions of the core and/or varying the composition of the sheathand/or core. These and other methods will be known to one of ordinaryskill in the art or can be determined by routine experimentation in viewof this disclosure.

In certain embodiments, the sheath can comprise from about 10% to about99% by weight, preferably from about 40% to about 95% by weight, andmore preferably from about 60% to about 90% by weight of the one or morehydrophobic matrix materials.

The sheath can further comprise one or more additional retardants or oneor more binders or plasticizers or excipients, or any combinationthereof, such as those described above for the adverse agent-containingcore.

5.7 Shell

The co-extruded dosage form of the present invention includes a shellcomprising an active agent. The dosage form can provide immediaterelease and/or controlled release of the active agent in vivo followingadministration. In certain embodiments, the dosage form provides acontrolled release of the active agent, such as an opioid agonist.Formulations and extrusion methods of manufacture of controlled releasedosage forms of opioid agonists are known in the art. For example, U.S.Pat. Nos. 5,958,452; 5,965,161; 5,968,551; 6,294,195 and 6,335,033, eachof which is expressly incorporated herein by reference in its entiretyfor all purposes, disclose controlled release opioid agonist dosageforms. The disclosure of one or more of such patents includes detailssuch as formulations, hydrophobic matrix materials, retardants, binders,plasticizers, and excipients, as well as extrusion methods for formingtablets, caplets and capsules containing MEMs, for controlled releaseopioid agonist dosage forms.

In certain embodiments, the active agent can be dispersed in a matrixwhich provides controlled release of the active agent in vivo followingoral administration. Any suitable controlled-release matrix can be usedto make the pharmaceutical compositions or dosage forms. Certaincontrolled-release matrices are known for oral formulations (See, e.g.,Remington's Pharmaceutical Sciences 1684-85 (18th ed. 1990), thedisclosure of which is expressly incorporated herein in its entirety forall purposes). In addition to the controlled release dosage formsdisclosed in the above-identified patents and publications, otherexamples of useful controlled-release matrices are described in U.S.Pat. Nos. 6,143,328; 6,063,405; 5,462,747; 5,451,409; 5,334,392;5,266,331, 5,549,912, 5,508,042, 5,656,295, 5,324,351, 5,356,467, and5,472,712, the contents of which are each expressly incorporated hereinby reference in its entirety for all purposes.

The controlled-release matrix can include fusible hydrophobicmaterial(s), optionally combined with hydrophilic material(s). Thehydrophobic fusible material(s) can be, for example, a hydrophobicpolymer or a natural or synthetic wax or oil, such as hydrogenatedvegetable oil or hydrogenated castor oil, which can, for example, have amelting point of from about 45° C. to about 100° C., and in oneembodiment from about 50° C. to about 90° C. The hydrophilic materialcan be a hydrophilic polymer such as a hydroxycellulose; a water solublefusible material, such as polyethylene glycol; or a water solubleparticulate material, such as dicalcium phosphate or lactose.

While any known co-extrusion method can be used to make controlledrelease dosage forms according to the present invention, the preferredmethod is melt co-extrusion of the ingredients with suitable matrixmaterials. For example, the shell comprising an active agent dispersedin a controlled-release matrix can be prepared by, e.g., extruding theactive agent with a suitable non-fusible material including, but are notlimited to, one or more of the following:

(a) Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers,protein-derived materials, nylon, acrylic resins, polylactic acid,polyvinylchloride, starches, polyvinylpyrrolidones, and celluloseacetate phthalate. Of these polymers, cellulose ethers, for example,substituted cellulose ethers such as alkylcelluloscs (e.g.,ethylcellulose), C₁-C₆ hydroxyalkylcelluloses (e.g.,hydroxypropylcellulose and hydroxyethyl cellulose), and acrylic resins(e.g., methacrylates such as methacrylic acid copolymers) can be used.The controlled-release matrix can conveniently contain from about 1% toabout 80% (by weight) of the hydrophobic and/or hydrophilic polymer.

(b) Digestible, long chain (C₈-C₅₀, in one embodiment C₈-C₄₀)substituted or unsubstituted hydrocarbons, such as fatty acids;hydrogenated vegetable oils; fatty alcohols, such as lauryl, myristyl,stearyl, cetyl or, in one embodiment cetostearyl alcohol; glycerylesters of fatty acids, for example, glyceryl monostearate; mineral oils;and waxes, such as beeswax, glycowax, castor wax, and carnauba wax.Hydrocarbons having a melting point of from about 25° C. to about 90° C.are used in one embodiment. Of these long chain hydrocarbon materials,fatty (aliphatic) alcohols are useful in one embodiment. Thecontrolled-release matrix can contain up to about 60% (by weight) of atleast one digestible, long chain hydrocarbon.

(c) Polyalkylene glycols. The controlled-release matrix can contain upto about 60% (by weight) of at least one polyalkylene glycol.

A suitable controlled-release matrix for use in the dosage form of theinvention can include one or more cellulose ethers or acrylic resins,one or more C₁₂-C₃₆ aliphatic alcohols, in one embodiment C₁₂-C₂₂aliphatic alcohols, and/or one or more hydrogenated vegetable oils. Aparticular suitable matrix includes one or more alkylcelluloses, one ormore C₁₂-C₃₆ aliphatic alcohols, in one embodiment C₁₂-C₂₂ aliphaticalcohols, and optionally one or more polyalkylene glycols. In anotherembodiment, the matrix contains from about 0.5% to about 60% by weight,and in another embodiment from about 1% to about 50% by weight, of thecellulose ether.

The acrylic resin can be, for example, a methacryl ate such asmethacrylic acid copolymer USNF Type A (EUDRAGIT L™), Type B (EUDRAGITS™), Type C (EUDRAGIT L 100-55™), EUDRAGIT NE 30 D™, EUDRAGIT E™,EUDRAGIT RL™, or EUDRAGIT RS™ (commercially available from Röhm PharmaGmbH, Weiterstat, Germany). In one embodiment, the matrix contains fromabout 0.5% to about 95% by weight of acrylic resin, and in anotherembodiment from about 10% to about 50% by weight of acrylic resin.

In the absence of polyalkylene glycol, the matrix in one embodimentcontains from about 1% to about 40% by weight, in another embodimentfrom about 2% to about 36% by weight of the aliphatic alcohol. Whenpolyalkylene glycol is present in the oral dosage form, then thecombined weight of the aliphatic alcohol and the polyalkylene glycol inone embodiment constitutes from about 2% to about 40% by weight, inanother embodiment from about 2 to about 36% by weight of the matrix.

The polyalkylene glycol can be, for example, polypropylene glycol or, inone embodiment, polyethylene glycol. The number average molecular weightof the polyalkylene glycol is in one embodiment from about 200 to about15,000 Daltons, and in another embodiment from about 400 to about 12,000Daltons.

The shell may also comprise one or more of the materials disclosed forinclusion in the core. For example, the shell may comprise one or moreof the hydrophobic matrix materials binders, retardants, plasticizersand/or excipients disclosed supra in Section 5.5.

5.8 Co-Extrusion Process

The present invention also relates to co-extrusion methods for preparinga pharmaceutical composition or dosage form. The invention includesprocesses which comprise co-extruding, such as melt co-extruding, a coreincluding an adverse agent; optionally a sheath which at least partiallysurrounds the core; and a shell including an active agent which at leastpartially surrounds the core, and, if present, the sheath. In certainembodiments, the co-extrusion process produces a multilayer extrudatesheet which is rendered into one or more particles of an appropriatesize which are then incorporated into one or more dosage forms,including but not limited to, tablets, caplets, or capsules, each ofwhich may comprise or contain a plurality of particles. In oneembodiment, the method comprises using a rolling punch to render themultilayer extrudate into particles or tablets.

Generally, methods of preparing active agent-containing compositions ordosage forms by extrusion are well known. See, for example, U.S. Pat.Nos. 5,958,452, 5,965,161 and 6,335,033, each of which is expresslyincorporated herein in its entirety for all purposes, which discloseknown methods for extruding and forming pharmaceutical dosage forms,including dosage forms comprising particles. Co-extrusion methods toform dosage forms containing an active agent are also known. See, forexample, U.S. Pat. Nos. 4,880,585 and 5,073,379, each of which isexpressly incorporated herein in its entirety for all purposes.

It is also known to form moldable co-extruded extrudate into tablets byusing devices such as a molding roll, a pinch device, a belt and aroller or tow rollers. See, for example, U.S. Pat. Nos. 6,120,802 and5,073,379, each of which is expressly incorporated herein in itsentirety for all purposes.

In accordance with the present invention, a co-extrusion process is usedto make multilayer pharmaceutical compositions or dosage forms includingan active agent and an adverse agent, which can be sequestered. In oneembodiment, the dosage form is made by a process which comprisesco-extruding a core, a shell and, optionally, a sheath, and renderingthe extrudate into particles using a rolling punch.

In one embodiment, the invention relates to methods of making a dosageform by: a) co-extruding a core comprising an adverse agent and a shellcomprising an active agent which at least partially surrounds the core,preferably which surrounds a majority of the core, more preferably whichsubstantially or completely surrounds the core, to form a multilayerextrudate sheet; and b) forming the multilayer extrudate sheet intodosage forms, such as tablets, caplets or a plurality of particles. Inone embodiment, the method comprises the use of a rolling punch torender the multilayer extrudate sheet into particles.

In another embodiment, the invention relates to methods of making adosage form by: a) co-extruding a core including an adverse agent; asheath, which at least partially surrounds the core, preferably whichsurrounds a majority of the core, more preferably which substantially orcompletely surrounds the core; and a shell including an active agent,which at least partially surrounds the sheath, preferably whichsurrounds a majority of the sheath, more preferably which substantiallyor completely surrounds the sheath, to form a multilayer extrudate sheetor laminate; and b) forming the multilayer extrudate sheet into dosageforms, such as tablets, caplets or a plurality of particles. In oneembodiment, the method comprises the use of a rolling punch to renderthe multilayer extrudate sheet into particles.

In one embodiment, the dosage form comprises a plurality of particlescomprising a core, optionally a sheath, and a shell which arc placed ina capsule, preferably a gelatin capsule.

In one embodiment, the present invention further relates to methods ofpreparing a dosage form including charging a core formulation includingan adverse agent and a hydrophobic matrix material into a firstextruder; charging a shell formulation including an active agent and ahydrophobic matrix material into a second extruder; heating andextruding the formulations through a multilayer die to form a multilayerextrudate sheet or laminate including an adverse agent core covered atleast partially by the shell comprising the active agent; and renderingthe multilayer extrudate sheet into dosage forms, such as tablets,caplets or a plurality of particles. In one embodiment, the method cancomprise the use of a rolling punch to render the multiplayer extrudateinto one or more particles or dosage forms.

An example of an apparatus useful for one embodiment the presentinvention includes two powder-feeder hoppers, one for loading theadverse agent core components and one for loading the shell components.The core components can include the adverse agent and the hydrophobicmatrix material, and optionally additional materials including, but notlimited to, additional retardants, binders, plasticizers, processingagents, and excipients, as described above. The shell componentscomprise the active agent and the hydrophobic matrix materials, andoptionally additional materials including, but not limited toretardants, binders, plasticizers, processing agents, and excipients, asdescribed above. The contents of each hopper are charged to an extruder.The outlet of each extruder is attached to a co-extrusion die orifice(all extruders are connected to the same co-extrusion die) that issized, dimensioned, and configured to be used in the co-extrusionprocess, thereby forming a multilayer extrudate sheet or laminate, withthe adverse agent in the core and the active agent in the shell. Incertain embodiments, the multilayer extrudate sheet is configured suchthat the shell covers the top and bottom of the core. The multilayerextrudate sheet is then rendered into dosage forms. In one embodiment,the method comprises the use of a rolling punch to render the multilayerextrudate sheet into particles or dosage forms.

In another embodiment, the invention further relates to methods ofpreparing a dosage form including charging a core formulation includingan adverse agent and a hydrophobic matrix material into a firstextruder; charging a sheath formulation including a hydrophobic matrixmaterial into a second extruder; and charging a shell formulationincluding an active agent and a hydrophobic material into a thirdextruder; heating and extruding the formulations in the first, secondand third extruders; co-extruding the formulations through a multilayerdie to form a multilayer extrudate sheet or laminate; and rendering themultilayer extrudate sheet into dosage forms or particles including acore comprising an adverse agent; a sheath which at least partiallycovers the core; and a shell including an active agent that at leastpartially covers the sheath.

An example of an apparatus useful for this embodiment of the inventionincludes three powder-feeder hoppers, one for loading the corecomponents, one for loading the sheath components and one for loadingthe shell components. The core components can include the adverse agentand the hydrophobic matrix material, and optionally additional materialsincluding, but not limited to, additional retardants, binders,plasticizers, processing agents, and excipients, as described above. Thesheath components can include a hydrophobic matrix material andadditional materials including, but not limited to, additionalretardants, binders, plasticizers and excipients as described above.Also, as stated above, the sheath components can include the activeagent and/or the adverse agent. The shell components can comprise theactive agent and the hydrophobic matrix materials, and optionallyadditional materials including, but not limited to retardants, binders,plasticizers, processing agents, and excipients, as described above. Thecontents of each hopper are charged to an extruder. The outlet of eachextruder is attached to a co-extrusion die orifice (all extruders areconnected to the same co-extrusion die) that is sized, dimensioned, andconfigured to be used in the co-extrusion of a multilayer sheet orlaminate, thereby forming a multilayer extrudate sheet or laminate withthe adverse agent in the core; a sheath which at least partiallysurrounds the core, e.g., at least on the top and bottom of the core;and a shell comprising an active agent that at least partially coversthe sheath, e.g., at least on the top and bottom of the sheath. In oneembodiment, the method comprises the use of a rolling punch to renderthe multilayer extrudate sheet into particles or dosage forms.

The specific details of the configurations and settings of the extrudersused to co-extrude the compositions and dosage forms are not critical tothe present invention. The extruder details set forth herein areexemplary. Each extruder can, for example, be equipped with single ortwin screws and heated barrels. Each screw extruder can, independently,be of the (i) counter-rotating (i.e., driven in opposite directions ofrotation) non-intermeshing; (ii) co-rotating (i.e., driven in the samedirection of rotation) non-intermeshing; (iii) counter-rotatingintermeshing; or (iv) co-rotating intermeshing type, or some combinationthereof. Each extruder can, independently, have a sole discharge portlocated at the end of its housing or a radial discharge port. Each screwextruder can, independently, have drive means at each end of the screwor a drive means present at only one end. Each screw extruder can,independently, have a length to diameter, or L/D, ratio of from 5-70,preferably from 20-60. Those in the art are familiar with such apparati,e.g., a Leistritz twin screw extruder having a vacuum attachment, aLeistritz Micro 18/GL 40D twin screw extruder, or a Warner & Pfleiderermodel ZSK-30 twin screw extruder.

The temperature of each individually adjustable barrel zone of eachextruder is set to the required temperature for a given formulation, andthe extruder can be allowed to thermally equilibrate, typically forabout 30 minutes. The inside pressure of the twin screw extruder can bemaintained from about 600 to about 980 mbar negative.

After a steady state temperature is attained, the contents of eachpowder-feeder hopper are fed into a separate pre-heated extruder,thereby forming in each extruder an intimately mixed molten masstypically from about 30° C. to about 200° C. in temperature, preferablyfrom about 50° C. to about 150° C., through heating and mixing, as it isdriven through a series of zones by intermeshing screws and kneadingelements. Optionally, a vent port can be present in the extruder. If itis desired to add a liquid component, independently of any powderedformulation, to a molten mass, the liquid can be injected into theextruder by any known means, for example, by an injection port suppliedby a positive displacement pump, such as a gear pump.

The molten masses exiting each extruder are connected to a co-extrusiondie orifice, which is optionally downstream of a combining block and/ora main gate adaptor, then passed through the die orifice(s), therebyforming a multilayer extrudate sheet or laminate including an adverseagent core; an optional sheath at least partially surrounding the core;and a shell at least partially covering the core, or if present, thesheath. Generally, the rotation speed, in rpm, of each extruder isadjusted such that their combined output, at the die orifice exit, isfrom about 1 to about 20 kg/hr or greater, for example from about 6 toabout 8 kg/hr. The rotation speed of each extruder is one of theparameters that can be adjusted so that the output of each extruderyields the desired ratio of the core to the shell and, optionally, thesheath.

The dimensions and/or cross-sectional profile of the die orifice can beadjusted to vary the thickness and shape of the resulting multilayersheet. For example, the die orifice is not limited to a rectangularcross-sectional profile, but can have a trapezoidal character (i.e.,where the width of the top of the extrudate is smaller than width of thebottom of the extrudate, or vice versa); can have some degree ofcurvature associated with the width and/or thickness of the multilayersheet or laminate (i.e., top and/or bottom sides can have concave and/orconvex curvature, such that the thickness changes across the width ofthe extrudate; in one embodiment, the die orifice opening has a veryoblate oval shape); or can have any combination thereof. For example, anorifice having a circular cross-section can be adjusted to provide amultilayer sheet or laminate having a diameter from about 0.1 mm toabout 50 mm, alternately from about 0.5 mm to about 20 mm, for examplefrom about 1 mm to about 10 mm.

The multilayer extrudate sheet or laminate produced from theco-extrusion process is thereafter conveyed away from the die orificeand solidified by methods known to those in the art, for example, usinga fan-cooled tunnel or a continuous movable belt upon which themultilayer extrudate sheet congeals, hardens, or cures upon cooling. Themultilayer extrudate sheet is directed to a suitable device to renderthe extruded multilayer extrudate into dosage forms, such as pluralityof particles, using a rolling punch device or by any method known in theart. Rendering the multilayer extrudate sheet into dosage forms canoccur before, during or after congealing/curing.

In a preferred embodiment, the multilayer extrudate sheet which resultsfrom the co-extrusion process is allowed to partially cool and congealand the multilayer extrudate is then calendared cut by a rolling punch,as shown in FIG. 2. Other methods for forming moldable co-extrudedextrudate into tablets or particles by using devices such as a moldingroll, a pinch device, a belt and a roller or tow rollers are known (see,for example, U.S. Pat. Nos. 6,120,802 and 5,073,379).

In one embodiment, the co-extruded multilayer extrudate is cut, pinched,or crimped to form a number of tablets or particulates, such as, forexample, those shown in FIG. 1, where the adverse agent-containing coreis substantially or completely enveloped by the sheath layer(s) and theshell layer(s). Advantageously, in a preferred embodiment, the action ofa rolling punch device crimps or pinches the shell and sheath layerssuch that the sheath substantially or completely surrounds the core andthe shell substantially or completely surrounds the sheath. In any case,the compositions of the core and the sheath should be formulatedaccordingly to limit or prevent the rate of in vivo release of thesequestered adverse agent.

In addition, it is to be understood that the tablets or particles can beany geometrical shape within a desired size range, such as a bead, aseed, a pellet, etc., depending the method of producing the tablets orparticulates from the co-extruded multilayer sheet or laminate. Forexample, where oral dosage forms arc desired, the shape can include, butis not limited to, spherical, ellipsoidal, cylindrical, modifiedcylindrical (e.g., having cylindrical sides with top and/or bottomcurvature; having a substantially flat top and/or bottom with the sideshaving some degree of curvature, or a combination thereof), oval,elliptical, or the like, or some combination thereof, where“cylindrical” can include not only circular cross-sections but also oneor more of the following cross-sections: triangular, square, rhomboidal,diamond, trapezoidal, pentagonal, hexagonal, octagonal, star-shaped(e.g., having 3, 4, 5, 6, or more points), or some combination thereof,including those shapes where the corners have been at least partiallyrounded. In one embodiment, the particulates formed can be ellipsoidalwith dimensions (height, length, and width) from about 0.1 mm to about3.0 mm. In another embodiment, the particulates formed can becylindrical with similar dimensions. In one embodiment, the tablets orparticles are hexagonal. The rendering of hexagonal tablets or particlesfrom an extrudable sheet can allow for a reduction in waste as comparedto, for example, round tablets or particles.

It will be apparent to one of ordinary skill in the art ofpharmaceutical extrusion that the compositions and dimensions of thecore, the optional sheath, and shell can be varied to achieve thedesired release rate of the active agent and to adequately sequester theadverse agent. For example, by changing the co-extrusion die exitorifice dimensions, the thickness of the core, sheath and shell can bevaried. In one embodiment, the thickness of the core, the optionalsheath and the shell can be adjusted to provide a particle with amaximum dimension of about 5.0 mm or less; in another embodiment, fromabout 3.0 mm or less. In certain embodiments, the thickness of the core,the sheath and the shell is from about 0.05 mm to about 3.0 mm; inanother embodiment, from about 0.2 mm to about 1.0 mm. The desiredthickness of the sheath can be determined, for example, by thedissolution rate of the hydrophobic matrix material and the thickness ofthe core. In one embodiment, the thickness of the sheath is from about0.05 mm to about 3.0 mm; in another embodiment, from about 0.1 mm toabout 1.0 mm. The thickness of the shell can be adjusted based upon, forexample, the shell composition and desired rate of release of the activeagent. In one embodiment, the thickness of the shell is from about 0.05mm to about 3.0 mm; in another embodiment, from about 0.1 mm to about1.0 mm. In one embodiment, the dosage form can comprise a plurality ofparticles having a size ranging from about 0.1 mm to about 3.0 mm in anydimension.

In one embodiment, the dosage form comprises a plurality of MEM's.Optionally, following cutting and/or punching, the particles can bepassed through a separator, for example, using #16 TBC (approximately0.054″) and #26 TBC (approximately 0.031″) opening screens, andcollected. In one embodiment, the particles are placed in hard or softgelatin capsules for oral dosage to patients.

FIGS. 1 a, 1 b and 1 c illustrate perspective views of three embodimentsof a co-extruded particle of the present invention. In each of FIGS. 1a, 1 b and 1 c, core 3 comprises an adverse agent and a hydrophobicmaterial. In FIG. 1 a, sheath 2, which comprises a hydrophobic material,completely covers and surrounds core 3. Shell 1 comprises an activeagent and a hydrophobic material, and completely covers and surroundssheath 2.

In the embodiment shown in FIG. 1 b, the sheath 2 comprises upper sheathcomponent 2 a and lower sheath component 2 b. The sheath 2 surrounds thetop and the bottom portions of core 3, but leaves a small amount of core3 exposed along the side of the particle. Similarly, the shell 1comprises uppers shell component 1 a and lower shell component 1 b.Shell 1 surrounds the top and the bottom of the sheath 2 while leaving asmall portion of the sheath 2 and/or the core 3 exposed along the sideof the particle.

In FIG. 1 c, the sheath 2 comprises upper sheath component 2 a and lowersheath component 2 b which surround the top and the bottom of core 3while leaving a small portion of core 3 exposed along the side. In thisembodiment, the shell 1 completely covers and surrounds both sheath 2and core 3.

FIG. 2 shows a non-limiting example of one method of forming the dosageform of the invention comprising the use of a rolling punch to renderthe multilayer extrudate into a plurality of particles. As illustratedin FIG. 2, a co-extruded multilayer extrudate sheet 16 exits theco-extrusion die. The multilayer extrudate comprises a core 3 comprisingan adverse agent, a sheath 2 comprising a hydrophobic material and ashell 1 comprising an active agent. The multilayer extrudate 16 isconveyed from the co-extrusion die exit orifice to a rolling punch 10which renders the multilayer extrudate 16 into a plurality of particles14. In certain embodiments, the shell and sheath are pinched or crimpedby the rolling punch to substantially encapsulate the core, thuscreating an ellipsoid-shaped multilayer particle. In certainembodiments, including but not limited to, where the multilayerextrudate is simply cut or is incompletely punched and crimped, anexposed area of the core and/or sheath can exist, such as at the sidesor edges of the dosage form or particle.

6. METHODS FOR ADMINISTRATION

The present invention is also directed to methods for treating acondition in a patient including administering a dosage form of thepresent invention to a patient in need of said treatment. The dosageform, can be, for example, an oral dosage form, such as a tablet orcapsule, or a rectal or vaginal dosage form, such as a suppository. Inone embodiment, the condition is pain and the dosage form includes anopioid and a sequestered opioid antagonist. In certain embodiments, thedosage form is administered to a patient twice a day, and in otherembodiments, once a day.

6.1 Amount Per Dosage Unit

In the dosage form of the present invention, the amount of the activeagent per dosage unit is that which is an effective amount for itsparticular indication and is independent of the amount of the adverseagent. For example, if the therapeutic agent is an opioid agonist, theamount of the opioid agonist in the dosage form of the present inventionis generally from about 1 mg to about 800 mg; in one embodiment fromabout 5 mg to about 160 mg. One of ordinary skill in the art can readilydetermine, without undue experimentation, the amount of therapeuticagent needed for a particular indication.

The amount of the adverse agent in the dosage form of the presentinvention is such that the adverse agent can give the intended adverseeffect if, when tampered with, a substantial amount of the adverse agentis released immediately from the dosage form and absorbed into ananimal's blood. When, upon tampering with the dosage form, the adverseagent is intended to reduce or eliminate one or more of thepharmacological effects of the active agent, such as euphoria, theamount of the adverse agent in the dosage form is at least sufficient toreduce or eliminate those effects of the active agent when both agentsare substantially or completely released from the dosage form andabsorbed into an animal's blood after tampering has occurred.

When the adverse agent is an opioid antagonist, such as naltrexone ornalmefene, the amount of the opioid antagonist present in a dosage formof the present invention can be from about 0.5 mg to about 50 mg. Theopioid antagonists cyclazocine and naltrexone, when administered orally,retain much of their efficacy with a long duration of action,approaching 24 hours. Amounts of less than about 10 mg of these opioidantagonists are typically used in oral formulations of the invention.

When, upon tampering, the adverse agent is intended to cause anundesired physiological reaction, such as emesis, the amount of theadverse agent in the dosage form is at least sufficient to cause sucheffect upon release after tampering has occurred.

For safety reasons, the amount of the adverse agent present in thedosage form should elicit the intended adverse effect without beingharmful to humans even if it is all immediately released.

In certain embodiments of the present invention, the ratio of thetherapeutic agent to the adverse agent in the dosage form can be fromabout 1:1 to about 50:1 by weight, in one embodiment from about 1:1 toabout 20:1 by weight. In certain other embodiments, the ratio can beabout 1:1 to about 10:1 by weight.

In non-limiting embodiments in which the opioid agonist is hydrocodone,the controlled release dosage forms can include analgesic doses fromabout 5 mg to about 80 mg of hydrocodone per dosage unit. Innon-limiting embodiments where the opioid agonist is hydromorphone, itcan be included in an amount from about 2 mg to about 64 mghydromorphone hydrochloride per dosage unit. In non-limiting embodimentsin which the opioid agonist is morphine, it can be present in the dosageform from about 2.5 mg to about 800 mg morphine per dosage unit. Innon-limiting embodiments in which the opioid agonist is oxycodone, thedosage forms can include from about 2.5 mg to about 160 mg oxycodone,and in another embodiment from about 20 mg to about 30 mg oxycodone perdosage unit. Controlled-release oxycodone formulations are known in theart. In a non-limiting embodiment, the opioid agonist can be tramadol inan amount from about 25 mg to 800 mg tramadol per dosage unit. Thedosage form can contain more than one opioid agonist, and the doses ofeach can be adjusted accordingly.

The term “unit dose” is defined for purposes of the present invention asthe total amount of dosage form needed to administer a single desireddose of active agent (e.g., opioid agonist) to a patient.

6.2 Methods for Vaginal or Rectal Administration

As noted above, the present invention is also directed to administrationof a dosage form comprising an active agent and an adverse agent, whichcan be sequestered, to a patient in need thereof in the form of asuppository for absorption through the vagina or rectum. Whenadministered as a suppository, the composition preferably includes asuppository base material. Any suppository base material can be usedprovided it does not dissolve the particulates. For example, cocoabutter is a traditional suppository base material, which can be modifiedby the addition of waxes to raise its melting point. One or morewater-miscible suppository base materials, such as polyethylene glycolsof various molecular weights, can be included. When administered as asuppository, the combined concentration of the first and secondplurality of particles in the suppository formulation is, typically,from about 5% to about 80% by weight of the composition.

6.3 Kits

The present invention is also directed to a kit containing at least onedosage form of the invention. In one embodiment, the dosage form ispresent in a container, e.g., a bottle or box. In another embodiment,the kit further includes a set of instructions directing the use of thedosage form to treat a patient, e.g., for pain. In one embodiment, theinstructions can be a printed label affixed to or printed on thecontainer. In another embodiment, the instructions can include a printedsheet inserted into the container or into the packaging which containsthe container. The instructions can also state that the dosage formand/or its usage are designed to reduce abuse, misuse or diversion ofthe dosage form.

7. EXAMPLES

The following example is set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, arc to be considered to fall within the scope of the presentinvention.

7.1 Example 1 Preparation of Particles Containing Opioid Agonist andSequestered Opioid Antagonist by Melt Co-Extrusion

Example 1 describes a prophetic example of a process which should besuitable for the preparation by melt co-extrusion of a particleincluding a core comprising an opioid antagonist, a sheath, and a shellcomprising an opioid agonist. The active agent is hydromorphonehydrochloride and the sequestered opioid antagonist is naltrexonehydrochloride. The top and bottom of the core is covered by a sheathwhich does not contain any hydromorphone or naltrexone. The formulationsof the feed to the core extruder, the sheath extruder and the shellextruder are provided in Table 1.

TABLE 1 Formulation Used to Prepare Sheathed Sequestered NaltrexoneHydrochloride Particles by Melt Co-extrusion. Ingredient Amount (mg)Core Formulation: 67 Naltrexone HCl 8 EUDRAGIT RS PO ™ 44 Stearylalcohol 7 Stearic acid 7 BHT 1 Sheath Formulation: 59 EUDRAGIT RS PO ™44 Stearyl alcohol 15 Shell Formulation: 120 Hydromorphone HCl 12EUDRAGIT RS PO ™ 76.5 Stearyl Alcohol 27 Ethyl cellulose 4.5 Total 246

The multilayer particle of Example 1 can be prepared by charging theformulation ingredients for the core, the sheath and the shell intothree separate extruders. For example, each formulation can be chargedto the powder-feeder hopper of a Leistritz twin screw extruder having avacuum attachment. Each extruder can be equipped with twin-screws and amulti-zone heated barrel. In each extruder, the initial zones,intermediate and final zones can be maintained at a target temperatureof about 30° C. to about 150° C. Each extruder can be allowed tothermally equilibrate for about 30 minutes. The inside pressure of eachtwin screw extruder can be maintained from about 600 to about 980 mbarnegative. The inlet of each extruder barrel is attached to the outletend of the respective powder-feeder hopper. The outlet of the separatecore, sheath and shell extruder barrels can be connected to theappropriate inlet orifice of a co-extrusion die to form a multilayerextrudate sheet or laminate. The rotation speed of each extruder can beset to a level to produce the desired combined output, at the dieorifice, such as about 5 to 15 kg/hr. The formulations can be heatedwith mixing until respective molten masses form. Each resultant viscousmass can then be extruded through the respective extruder barrel to therespective co-extrusion die inlet ports to form the multilayer extrudatesheet containing the core, the sheath and the shell. The multilayerextrudate sheet can then be transported on a continuous movable belt toa rolling punch device as it partially cools and congeals. In oneembodiment, the partially congealed hardened multilayer sheet can bepelletized with a rolling punch device into hexagonal particles eachhaving a major axis diameter of about 0.1 to about 3.0 mm, a minor axisdiameter of about 0.1 to about 3.0 mm, and a thickness of about 0.1 toabout 3.0 mm. In these particles, the average thickness of the core canbe about 0.05 to about 3.0 mm; the average thickness of the sheath canbe about 0.05 to about 3.0 mm; and the average thickness of the shellcan be about 0.05 to about 3.0 mm.

The in vitro rate of dissolution of the dosage form can be measuredusing the USP basket method. The apparatus can consist of a USP Type 1basket (100 rpm). The particulate dosage forms are contacted with 700 mLsimulated gastric fluid (SGF), (pH 1.2 without enzyme) at 37° C. for onehour. Thereafter, the particulate dosage forms are contacted with 900 mLsimulated intestinal fluid (SIF) (pH 7.5 without enzyme) for theduration of the test. The rate of dissolution is determined by assayingeach of the fluids using HPLC.

The amount of adverse agent released in vivo is expected to be less thanan amount which will significantly affect the pharmaceutical effect ofthe active agent and less than an amount which will elicit anysignificant unpleasant physiological effects.

All patents, applications, publications, test methods, literature, andother materials cited above are hereby incorporated herein by referencein their entirety for all purposes.

1-11. (canceled)
 12. A co-extruded dosage form comprising: a corecomprising an adverse agent; a sheath comprising a hydrophobic materialwhich surrounds at least a portion of the core; and a shell comprisingan active agent which surrounds at least a portion of the sheath. 13.The co-extruded dosage form of claim 12, wherein the core furthercomprises a hydrophobic material.
 14. The co-extruded dosage form ofclaim 12, wherein the sheath surrounds a majority of the core; and theshell surrounds a majority of the sheath.
 15. The co-extruded dosageform of claim 12, wherein the shell further comprises a hydrophobicmaterial.
 16. The co-extruded dosage form of claim 12, wherein thehydrophobic material comprises a material selected from the groupconsisting of acrylic and methacrylic acid polymers and copolymers,alkylcelluloses, natural and synthetic waxes, water insoluble waxes,fatty alcohols, fatty acids, hydrogenated fats, fatty acid esters, fattyacid glycerides, hydrocarbons, hydrophobic and hydrophilic polymershaving hydrocarbon backbones, and mixtures of any two or more of theforegoing.
 17. The co-extruded dosage form of claim 16, wherein thehydrophobic material comprises an ammonio methacrylate copolymer. 18.The co-extruded dosage form of claim 12, wherein the dosage from is anoral dosage form.
 19. The co-extruded dosage form of claim 18, whereinthe oral dosage form is a tablet or caplet.
 20. The co-extruded dosageof claim 18, wherein the oral dosage form is a capsule containing aplurality of particles.
 21. The co-extruded dosage form of claim 12,wherein the active agent is an opioid agonist and the adverse agent isan opioid antagonist.
 22. The co-extruded dosage form of claim 21,wherein the opioid agonist is selected from the group consisting ofalfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacyl morphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metophon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tramadol,tilidine, pharmaceutically acceptable salts thereof, and mixtures of anytwo or more of the foregoing.
 23. The co-extruded dosage form of claim21, wherein the opioid agonist is selected from the group consisting ofmorphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone,dihydrocodeine, dihydromorphine, pharmaceutically acceptable saltsthereof, and mixtures of any two or more of the foregoing.
 24. Theco-extruded dosage form of claim 21, wherein the opioid antagonist isselected from the group consisting of cyclazocine, naloxone, naltrexone,nalmefene, nalbuphine, nalorphine, cyclazacine, levallorphan,pharmaceutically acceptable salts thereof, and mixtures of any two ormore of the foregoing.
 25. The co-extruded dosage form of claim 21,wherein the opioid antagonist is selected from the group consisting ofnaloxone, naltrexone, nalmefene, pharmaceutically acceptable saltsthereof, and mixtures of any two or more of the foregoing.
 26. Theco-extruded dosage form of claim 21, wherein the dosage form providescontrolled release of the opioid agonist following administration to apatient.
 27. The co-extruded dosage form of claim 21, wherein the dosageform releases about 0.5 mg or less of the opioid antagonist in vivofollowing administration to a patient.
 28. The co-extruded dosage formof claim 21, wherein the dosage form releases about 0.05 mg or less ofthe opioid antagonist in vivo following administration to a patient. 29.A method for treating pain in a patient, comprising administering aco-extruded dosage form according to claim 12 to a patient, wherein theactive agent is an opioid agonist and the adverse agent is an opioidantagonist.
 30. A kit for treating pain in a patient, comprising: a) aco-extruded dosage form according to claim 13, wherein the active agentis an opioid agonist and the adverse agent is an opioid antagonist; andb) a printed set of instructions directing the use of the dosage form totreat pain in a patient. 31-65. (canceled)